Evidence supporting a relationship between depression and cardiovascular disease (CVD) is strong, but as of yet it is unclear how depression affects cardiovascular health (CVH) or if treating depression improves CVH. The lack of CVH improvement associated with successful depression treatment could be due to comorbid conditions not being addressed, especially nicotine dependence. Depression and nicotine dependence are highly comorbid, and bi-directionally causal and maintaining. Given this relationship, it may be critical to treat depression and nicotine dependence in tandem to achieve the greatest improvement in CVH. In the proposed research, it is hypothesized that depression remission and smoking cessation will interact to improve CVH above and beyond the additive effects of CVH improvements related to positive changes in these risk factors separately. A potentially valuable approach to studying the interaction of depression and nicotine dependence with CVH may be to leverage data from both long-term observational and short-term experimental research, as proposed in this application. First, using data from a prospective cohort study (Coronary Artery Risk Development in Young Adults [CARDIA] study), the association between patterns of depression and smoking over 25 years will be evaluated in relation to CVH. Second, as an experimental comparison to the observational study, CVH following depression remission and smoking cessation will be evaluated within the context of a randomized controlled trial (RCT) of targeted treatment for smokers with major depression. In both studies, CVD risk will be evaluated using clinical assessment tools, physiological indices of CVH, and CVH- relevant behaviors (e.g., physical activity). This research takes a translational approach to evaluating the relationship between depression and CVH, while accounting for nicotine dependence, by selecting measures for analysis in the RCT based on measures found to be relevant in the CARDIA study. This approach will provide information about how long-term, naturally resolving depression and nicotine dependence influences CVH as well as how a short-term, targeted treatment for comorbid depression and nicotine dependence can improve CVH. This will be the first study to examine the potential interactive effects of simultaneous depression remission and smoking cessation on CVH in high-risk individuals without CVD. Clinical interventions targeting healthy, high-risk populations, such as persons with depression who are nicotine dependent, can serve as a critical complement to public health CVD prevention efforts. These results would have implications for increasing the effectiveness of multiple behavior change interventions for improving CVH and ultimately preventing CVD.